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Kidney Week

Abstract: PO0620

Proximal Tubule Albumin Uptake: Potential Role for Endothelin System in Sickle Cell Disease Mice

Session Information

  • CKD Mechanisms - 1
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Kasztan, Malgorzata, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Pollock, David M., University of Alabama at Birmingham, Birmingham, Alabama, United States
Background

Elevated plasma endothelin-1 (ET-1) reported in sickle cell disease (SCD) patients correlate with microalbuminuria, a major mortality risk factor in SCD. ET-1 contributes to glomerular and tubular injury in SCD, as evidenced by increased glomerular permeability to albumin and urinary excretion of tubular injury markers. Although selective ETA receptor antagonism reduces albuminuria in humanized sickle cell (HbSS) mice, the mechanism of this action remains unclear. The aim of the study was to determine whether selective ETA receptor antagonism prevents albuminuria by preserving the expression of tubular albumin-associated transporters in proximal tubule (PT) cells.

Methods

Male C57BL/6 or HbSS and genetic control (HbAA) mice were used to determine the effect of ET-1 on the expression of proximal tubule albumin trafficking mediators, such as megalin and NHE-3.

Results

Exposure of primary mouse PT cells to ET-1 (50nM) for 8h decreased megalin (53% reduction) and doubled NHE-3 expression. Pre-treatment with the ETA antagonist, BQ123 (1 μM), preserved megalin expression and had no effect on NHE-3. Moreover, selective ETB receptor blockade (BQ788, 1 μM) prevented ET-1-mediated increase in NHE-3 expression. Primary PT cells isolated from HbSS mice showed decreased megalin mRNA expression as well as protein abundance relative to HbAA PT controls. Ten-week treatment with selective ETA receptor antagonist (10mg/kg/day) preserved expression of megalin at control levels. There were no differences in NHE-3 mRNA expression in HbSS PT cells regardless the treatment. Interestingly, PT cells from HbSS cultured with HbSS plasma and ET-1 (10nM) had decreased NHE-3 protein abundance compared to non-treated cells.

Conclusion

These results potentially uncover a novel role for ET-1 in PT albumin handling and suggest that PT ET-1 receptor signaling contributes to albuminuria in SCD.

Funding

  • Other NIH Support